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ONdrugDelivery SEPTEMBER 2013ISSUE NO 44ISSN-2049-145X

DRUG DELIVERY & FORMULATIONSOLUTIONS & SERVICES

2

CONTENTS

Keeping up with the Biopharmaceutical MarketHans Ole Klingenberg, Director, Global MarketingNovozymes Biopharma 4-6

Interview Professor Marc BrownMedpharm 10-13

Disposable Patch Pump for Accurate DeliveryDr Laurent-Dominique Piveteau, Director, Business DevelopmentDebiotech 16-20

Great Inventions that Trick Nature – New Delivery System Optimises Bladder Cancer Treatment by Increasing Dwell TimeDr Sari Prutchi Sagiv, Marketing DirectorTheraCoat 22-26

Prefilled Syringes for Viscous FormulationsDr Mahesh Chaubal, Senior Director, Drug Development, R&D Medical ProductsBaxter Healthcare Corporation 27-28

Protein Solubility Can Be Enhanced at Various Points Along the Production PipelineDr Michelle Amaral, Science Writer/PR ConsultantSoluble Therapeutics 30-31

www.ondrugdelivery.com Copyright © 2013 Frederick Furness Publishing Ltd

The views and opinions expressed in this issue are those of the authors. Due care has been used in producing this publication, but the publisher makes no claim that it is free of error. Nor does the publisher accept liability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication.

Front cover image “MEMS pumping unit of the Debiotech NanoPUMP™ device” supplied by Debiotech SA. Reproduced with kind permission. Debiotech’s feature article appears in this issue, page 16.

ONdrugDelivery Issue No 44, September 2013

“Drug Delivery & Formulation Solutions & Services”

This edition is one in the ONdrugDelivery series of pub-lications from Frederick Furness Publishing. Each issue focuses on a specific topic within the field of drug deliv-ery, and is supported by industry leaders in that field.

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& Services 2014

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ONdrugDelivery Magazine is published by Frederick Furness Publishing Ltd. Registered Office: The Candlemakers, West Street, Lewes, East Sussex, BN7 2NZ, United Kingdom. Registered in England: No 8348388.VAT Registration No: GB 153 0432 49.ISSN 2049-145X printISSN 2049-1468 pdf

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Mix with the worldof pharma, products, people and packaging

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www.ondrugdelivery.com Copyright © 2013 Frederick Furness Publishing Ltd4

Hans Ole KlingenbergDirector, Global Marketing

Contact:Sally Vernon Customer Communications Manager E: [email protected]

Novozymes Biopharma US, IncOne Broadway, 14th FloorCambridge, MA 02142United States

T: +1 617 401 2500 (US Sales Office)T: +45 4446 2896 (EU Sales Office)E: [email protected]

www.biopharma.novozymes.com

In this article, Hans Ole Klingenberg, Director, Global Marketing, Novozymes Biopharma, shares how the company is helping its clients meet changing industry demands.

KEEPING UP WITH THE BIOPHARMACEUTICAL MARKET

The pharmaceutical biologics market is a

significant and rapidly developing field,

populated with a range of players, from large

companies to fast-growing start-ups. Exciting

technology and impressive growth predictions

characterise the market. The market for biologics

is moving increasingly towards the use of

these kinds of medical products as blockbuster

treatments, assisting in the treatment of chronic

conditions, such as arthritis and diabetes, and

this step forwards is reflected in some exciting

market predictions. At the end of 2012, one

estimate puts the global biologics market at

US$176.4 billion (£110 billion), with expected

CAGRs of over 9.5%.1

In a market this size, there are huge

opportunities – both financial and in solving

unmet clinical needs – in fields such as

oncology, infectious and inflammatory diseases,

and paediatric vaccines. But there are also

significant challenges. Increasingly, companies

are being asked to look into creating ‘more

for less’ – safer, more tailored therapies on

smaller budgets and in quicker timeframes.

Manufacturers must improve and streamline

their processes in order to get the most from

this increasingly competitive field. Doing so

can ensure their success in a market which is

evolving and growing, fuelling the development

of a greater number of more innovative therapies

that can make a real impact on

healthcare around the world.

CHALLENGES OF AN EVOLVING MARKET

Safety has always been a

top priority within the biologics

market, especially with some

studies suggesting these types

of therapies pose a heightened

risk of adverse effects compared

with other treatments.2 Under

this scrutiny, and after several

high-profile product recalls,

the safety record and testing

of proposed treatments is being

exposed to even greater examination from

governments and regulatory agencies.

This tight monitoring of safety levels

is a trend that is likely to continue, and

manufacturers are encouraged to do everything

possible to ensure the purity and safety of their

end products right from the initial formulation

stages. This involves knowing the sources of

components, being certain of their purity and

quality and, when scaling-up from laboratory

“INCREASINGLY, COMPANIES ARE

BEING ASKED TO LOOK INTO CREATING

‘MORE FOR LESS’ – SAFER, MORE

TAILORED THERAPIES ON SMALLER

BUDGETS AND IN QUICKER TIMEFRAMES.

MANUFACTURERS MUST IMPROVE

AND STREAMLINE THEIR PROCESSES IN

ORDER TO GET THE MOST FROM THIS

INCREASINGLY COMPETITIVE FIELD”

Copyright © 2013 Frederick Furness Publishing Ltd www.ondrugdelivery.com

formulation to manufacturing, ensuring batch-

to-batch consistency.

A second, related challenge becoming

increasingly important in the formulation stages

of therapies is the stability of manufactured

molecules. Not only does this impact on the

safety of the end product – stable therapies

remain within the therapeutic range in a patients

system for longer, increasing the patient’s

tolerance to the drug and reducing side effects –

but by creating molecules which remain active

for longer, lower and less frequent dosage

levels for patients can be achieved, resulting in

increased patient adherence.

This is an issue which is particularly

prevalent when working with manufactured

peptides and proteins, often hampered by their

characteristically short half-lives. While natural

antibodies have a recirculation half-life of

around 250-300 hours, engineered antibodies

struggle to reach 25% of this level. It is

therefore unsurprising that many companies and

regulatory agencies are pushing for technologies

to assist in the creation of more stable therapies

with longer half-lives and dosage extension.

By creating these, there is also hope that an

increased number of treatments with tuneable

half-lives can be developed, allowing therapies

to be fine-tuned to suit patients’ needs without

the requirement of a complicated dosing regime.

Achieving more control over drug release would

mean that dosing frequency could be reduced

and stable levels maintained in the body,

increasing patient safety and adherence. This is

therefore another ideal that is being pushed for

by companies throughout the pharmaceutical

industry, and is sure to play a major role in the

development of the market.

However, it must not be forgotten that all of

these obstacles – safety, stability and flexibility

– need to be overcome in a manufacturing

environment. As previously stated, methods

must be easy to scale-up to industry-level

manufacturing once they have gone through

a laboratory setting. Companies are aiming to

make their processes cost-efficient and reduce

the time to market, and even then it often takes

several years for a potential therapy to reach

clinical trials. The main challenge to be found

is achieving all of these goals simultaneously.

ENSURING PURITY AND SAFETY

In order to develop safer and more innovative

products, there are several techniques available

to formulators. One such solution is to remove

as many animal-derived components as possible

from product formulations. Quality control

on products is becoming subject to stricter

governing from regulatory bodies, aiming to

improve safety and minimise risk by encouraging

the use of animal-free treatment components.

For example, traditional sources of hyaluronic

acid (HA) – often used in applications such

as trabeculectomy, retinal reattachment and

trauma surgery – include rooster comb extract

and various attenuated strains of Streptococcus

bacteria. These are further purified using harsh

organic solvents, and could potentially result

in contamination risks from animal-derived

proteins, viruses or endotoxins.

In order to assist its clients and help them

to provide purer, safer treatment therapies,

Novozymes Biopharma provides an alternative

to the traditional animal-derived sources of HA.

This has been achieved through the development

of a Bacillus fermentation process. Bacillus

subtilis is a non-pathogenic host whose products

are categorised as “Generally Recognized as

Safe” (GRAS) by the US FDA. HA derived in

this manner shows low amounts of nucleic acids,

proteins, bacterial endotoxins, exotoxins and

microbial contamination, and hypersensitivity

reactions in patients are therefore reduced.

The use of Bacillis-dervied HA is just one

method by which Novozymes Biopharma is

helping the industry move towards the production

of safer, more sustainable product formulations.

STABILISING DRUG FORMULATIONS

The importance of producing a stable

molecule for treatment therapies has already been

recognised in this article. Optimising the product

formulation, for example by adding stabilising

excipients, provides a valuable solution for

formulators who wish to stabilise their protein-

based treatment and vaccine formulations.

However, many methods for stabilisation

require multiple excipients, leading to a large

amount of time and resources being dedicated

to this by developers. Combinations of human

serum albumin (HSA) and a variety of sugars,

amino acids and detergents (SADs) have been

found to be useful in stabilising both protein-

based treatments and vaccine formulations, but

a method to reduce the number of excipients

needed to stabilise therapeutic proteins is highly

sought after.

rAlbumin from Novozymes Biopharma,

has been shown to stabilise such formulations

by protecting against surface adsorption,

inhibiting aggregation and also functioning as

an antioxidant. This combination reduces the

amount of treatment molecule lost throughout

the body before it reaches its therapeutic target,

leading to an increased efficiency and improved

results at lower dosage. Using rAlbumin,

formulation scientists can simplify their

strategies and reduce the number of excipients

needed to stabilise a protein-based treatment

or vaccination candidate. The knock-on effect

is less time spent refining combinations of

excipients and therefore streamlining of the

formulation and manufacturing processes.

SUSTAINED-RELEASE AND FLEXIBLE HALF-LIVES

Half-life extension is an area that has

captured the attention of many formulators

within the biopharmaceutical market. Peptide

and proteins, especially, do not have sufficient

half-lives to allow their use as effective

treatments in a clinical setting. In these cases the

frequency and high doses that would be required

to achieve a therapeutic effect are likely to

make them intolerable to patients. Extending

the half-lives of manufactured molecules, and

acquiring technologies that will facilitate greater

control of the therapeutic half-life of drug

candidates, is therefore an important goal of

many pharmaceutical companies.

In response to this, Novozymes Biopharma has

created a tuneable half-life extension technology

in the form of Albufuse® Flex and Recombumin®

Flex (currently in pivotal Phase III trials with

GSK and TEVA) based on a series of engineered

human albumins with modified binding to the

human FcRn receptor. The combination of these

engineered albumins with a drug candidate offers

the potential for tuneable control of the therapeutic

half-life in a manner previously unachievable

with native human albumin and other HLE

technologies, such as PEGylation and Fc and

albumin fusion proteins. Together with reducing

dosing frequencies from days to weeks, this is the

only technology using natural functioning, anima-

free recombinant albumin.

5

“IT MUST NOT BE FORGOTTEN THAT ALL OF THESE OBSTACLES

– SAFETY, STABILITY AND FLEXIBILITY – NEED TO BE OVERCOME

IN A MANUFACTURING ENVIRONMENT ... METHODS MUST BE

EASY TO SCALE-UP TO INDUSTRY-LEVEL MANUFACTURING”


EFFICIENT, SCALABLE MANUFACTURING

By including Novozymes Biopharma

components in formulations, pharmaceutical

manufacturers have access to a sustainable supply

of components at a large scale. This ready supply

should allow them to continue with production in

an efficient and streamlined fashion.

With 25 years’ worth of experience in

industrial-scale manufacturing, Novozymes

Biopharma ensures that its facilities can provide

a ready supply of high-quality, standardised

product, delivering completely scalable

product manufacture to clients. Its large-

scale manufacturing plant has the capacity for

fermentation of volumes from 5-27,000 litres.

This ready supply ensures clients can achieve

a streamlined process that gets their potential

therapies towards clinical trials, and eventually

to market, as quickly as possible.

CONCLUSION

With ever more innovative products coming

onto the market, and more emphasis being placed

on providing tailored, safe therapies in a shorter

timeframe, it is an exciting and challenging

time to be part of the biopharmaceutical arena.

Novozymes Biopharma has developed some

unique and innovative technologies to help its

clients meet the needs of a rapidly evolving

market, and work to provide them with additional

regulatory support and security of supply.

Many challenges and obstacles need to

be overcome, but it is generally agreed that

biologics will be one of the cornerstones of

future therapies, and will play a role in treatment

of several major diseases. Consequently,

creating safe, stable therapies is the aim of

many scientists within drug formulation, half-

life extension and medical device applications.

Novozymes Biopharma’s solutions and

expertise are tailored to match the needs of this

highly driven market.

REFERENCES

1. Sheela AK, “Biologics Market – G7 Industry

size, market share, trends, analysis and

forecasts 2012-2018”. Transparency Market

Research (November 10, 2012).

2. Giezen TJ, Mantel-Teeuwisse AK, Straus

SJJM, Schellekens H, Leufkens HGM, Egherts

ACG, “Safety-related regulatory actions for

biologicals approved in the United States

and the European Union”. J Am Med Assoc,

2008, Vol 300, pp 1887–1896.

ABOUT THE AUTHOR

Hans Ole Klingenberg is Director for the Global

Marketing group in Novozymes Biopharma.

Hans Ole has been with Novozymes for more

than ten years and has through his time at

Novozymes held various positions in the area

of corporate business development, with a focus

on the establishing new business entities for

Novozymes in the biopharmaceutical industry.

Hans Ole has since 2007 been working in

Novozymes’ Biopharma business with a focus

on marketing, and is commercially responsible

for establishment of Novozymes’ new

Hyaluronic Acid business franchise. Hans Ole

has a background from Copenhagen University,

with a bachelor in chemistry and master in

Economics. He is based in Denmark.

ABOUT NOVOZYMES

Novozymes is the world leader in bioinnovation.

Together with customers across a broad array

of industries we create tomorrow’s industrial

biosolutions, improving our customers’

business and the use of our planet’s resources.

With over 700 products used in 130 countries,

Novozymes’ bioinnovations improve industrial

performance and safeguard the world’s resources

by offering superior and sustainable solutions

for tomorrow’s ever-changing marketplace.

Novozymes’ natural solutions enhance and

promote everything from removing trans fats

in cooking, to advancing biofuels to power the

world tomorrow. Our never-ending exploration

of nature’s potential is evidenced by over

6,000 patents, showing what is possible when

nature and technology join forces. Our 5,000+

employees working in research, production and

sales around the world are committed to shaping

business today and our world tomorrow.

6

“MANY METHODS FOR STABILISATION REQUIRE MULTIPLE

EXCIPIENTS, LEADING TO A LARGE AMOUNT OF TIME AND

RESOURCES BEING DEDICATED TO THIS BY DEVELOPERS ... A

METHOD TO REDUCE THE NUMBER OF EXCIPIENTS NEEDED TO

STABILISE THERAPEUTIC PROTEINS IS HIGHLY SOUGHT AFTER”

“THE COMBINATION OF THESE ENGINEERED ALBUMINS WITH

A DRUG CANDIDATE OFFERS THE POTENTIAL FOR TUNEABLE

CONTROL OF THE THERAPEUTIC HALF-LIFE IN A MANNER

PREVIOUSLY UNACHIEVABLE WITH NATIVE HUMAN ALBUMIN

AND OTHER HLE TECHNOLOGIES, SUCH AS PEGYLATION AND

FC AND ALBUMIN FUSION PROTEINS”

IN WHICH EDITIONSHOULD YOURCOMPANY APPEAR?WWW.ONDRUGDELIVERY.COM

Overlookedsomething?Remember when it comes to reducing drug dosing frequency, the natural choice is albumin.

Extend the half-life of your drug from “days to weeks” using the only technology based on albumin, a natural non-immunogenic plasma protein with a proven and safe regulatory profile. Differentiate your drug with Novozymes’ Albufuse® Flex and Novozymes’ Recombumin® Flex - a broadly applicable and easily assessed platform with patent life beyond 2030.

Designed by Nature. Improved by Novozymes.

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PATIENT-CENTRIC DESIGN

DIFFERENTIATION

RIGOROUS DESIGN & MANUFACTUREREGULATORY EXPERTISE

ASSURANCE


Q: What do you see as the key drivers that have fuelled the topical and transdermal space over the last decade?

According to BCC Research, the global derma-

tology market reached $15.8 billion (£9.9 billion)

in 2012, and is expected to reach $18.5 billion by

2018, registering a compound annual growth rate

(CAGR) of 2.8%.1 IMS Health would have us

believe we are there already with a market value

of $18bn in 2008. Vagaries aside as to what clas-

sifies as dermatology or cosmeceuticals, the area

continues to grow thanks largely to the cross-

fertilisation of biotherapeutics from other indi-

cations to treat psoriasis, such as the anti-TNF

antibodies and new interleukin antibodies, such

as Centocor’s Stelara, and Amgen’s brodalumab,

which is due to start Phase III. Most dermato-

logical diseases are common, chronic and costly,

fulfilling the criterea that pharma like. Add to

this the increasing use of transdermal delivery

devices to deliver active compounds systemically

via non-invasive patches, then you have burgeon-

ing interest in both diseases of the skin and how

drugs can be delivered to or across the skin. The

North American drug delivery market is expect-

ed to register a CAGR of 8.9% between 2012 and

2017, and transdermal systems are expected to

make up a significant percentage of this.2

Trends in pharmaceutics over the recent past

have rapidly changed the presentation of the

drugs we use today. There have been several

shifts driven by patient and clinician choice and

compliance. A drive in innovation with drug

delivery devices themselves and improvements

in primary packaging now form an integral part

of the overall product, for example metered-dose

inhalers, transdermal patches and nasal sprays.

Formulations that target extended- or modified-

release profiles have also become standard dos-

ing options where the active may have a short

plasma half-life, to avoid multiple daily dosing

or where systemic exposure to smaller amounts

of the drug over a longer period is desirable e.g.

anti-infectives, NSAIDs and mental disorder

drugs. New demands are being made of formula-

tion scientists from marketing, compliance, life-

cycle management and distribution departments

that require new dosage forms that provide

competitive differentials, convenience to the end

user, enhanced safety, stability and efficacy or to

reinvigorate mature drugs for new uses in other

indications or in the same indication but with a

different posology. As such the design and use

of topical and transdermal dosage forms is now

entering a new phase of innovation.

We have seen a large movement in the

demand for new formulations for locally applied

products driven by a number of factors.

Firstly, more actives are being promoted for

local delivery as part of lifecycle management

having originally started life as oral forms,

such as terbinafine. Secondly dermatology is

becoming an interesting space for big pharma

again due to the repositioning and success

of such blockbuster drugs as the anti-TNF

biologics for psoriasis. Humira, Embrel and

Remicade now hold positions one, two and

four in worldwide sales.3 Most of the important

dermatological and inhaled drug indications

are chronic and by their very nature need long-

term repeated administration which usually

means lifetime treatment; this can be a very

lucrative business. Third, innovation in trans-

dermal patches and devices has opened up a

new multi-billion pound market for extended

or modified drug release.

Finally, most companies do not have the

internal topical and transdermal formulation

and testing expertise needed to innovate their

existing drug franchises. In order to develop

more versatile dosage forms with improved

delivery and aesthetics, which will be funda-

mental to their subsequent market success, these

companies look to outsource. For example, in

topically applied formulations in dermatology,

patients obviously want a cure but they do not

necessarily want to compromise their physical

appearance to get one. Such locally applied

formulations therefore have to meet criteria

that other oral or parenteral formulations do not

need to consider. The art of this area of formula-

tion science is long dead in big pharma.

INTERVIEW PROFESSOR MARC BROWN, MEDPHARM

TOPICAL & TRANSDERMAL DRUG DELIVERY – HAVE WE ONLY JUST SCRATCHED THE SURFACE?

ONdrugDelivery Magazine spoke with Professor Marc Brown, Chief Scientific Officer, Chief Operating Officer and Co-Founder of MedPharm, the topical and transdermal formulation development specialist, about how new drug delivery technologies may open yet more horizons for pharmaceutical companies in the near future. Here, he shares his insights on topical and transdermal drug delivery and presents one new platform technology, MedSpray, which was developed by MedPharm and is now available to clients under licence.


Q: So what is so different about the skin as a route for drug delivery as opposed to say the intestinal lining?

Where do I begin! The skin first and foremost is

the primary barrier we have between our precious

internal organs and our external environment. It’s

also a watertight container. We would not want

to swell up to the size of a balloon every time we

jumped into the bath or swimming pool. Like a

lot of things in nature it is far more complex in

terms of design than people think or understand.

It’s our largest organ and primary defence against

invading pathogens, toxic chemicals and ionising

radiation. The skin is crammed with sensors and

responds to external humidity changes and insult

or trauma. It has a complex homeostatic system

to help us maintain a stable core temperature

as well as maintain the integrity of the barrier

function and repel invaders and repair damaged

tissue. It has a highly efficient immune response

system comprising both cell-mediated and innate

immune responses. That is why it can at times be

so sensitive to inflammation from an insect bite

or other allergen. The skin can recruit T-cells

and other inflammatory cells at the first sign

of damage through incredibly fast chemotactic

responses driven by local cytokine production. A

lot of skin diseases such as psoriasis and cancers

hijack this system.

Q: It seems a pretty impregnable fortress then?

Yes but having said that, it is permeable once

you can penetrate the stratum corneum (SC). The

main defence is the ‘bricks and mortar’ com-

pacted design of flattened corneocytes surrounded

by a lipid matrix in the SC (see Figure 1) which

makes it very hydrophobic (Elias, 1983; Suhonen

et al, 1999). As such, certain chemicals under

certain conditions such as primarily lipophilic

compounds with a molecular weight <500 Da

have the best chance of penetration. The potency

of any drug also needs to be considered. However,

we have developed some techniques and systems

that can modify these established rules.

Methods for overcoming the barrier are

generally considered to be either: chemical/pas-

sive, for example the use of penetration enhanc-

ers, prodrug and eutectic systems; or physical/

active such as iontophoresis, electroporation,

ultrasound, microneedles, application of local

heat, needleless injection and combinations

thereof. Both techniques change either or both

of the diffusion rate of the active and/or the per-

meability of the SC. Up until relatively recently

and despite this understanding, the actual effi-

ciency of delivering an active to the skin from

many traditional formulations such as creams/

emulsions and ointments was very poor as

typically a large proportion of the drug remains

trapped in the vehicle (Barry, 1991; Shah

et al, 1989). However, technologies such as

MedSpray® have improved things significantly.

If the barrier can be overcome there are

unique advantages of delivering a drug to,

and across, the skin when compared with oral

and parenteral delivery. These include the

avoidance of hepatic first-pass metabolism,

improved patient compliance, reduced toxicity

and ease of access to the affected site for locally

acting drugs. Why deliver a drug to treat a skin

condition orally? Why risk exposing delicate

organs to the possible off-site toxicities and

wasting the majority of the drug in circulation

unless you really have to?

Q: What specific parameters do you need to address when optimising the delivery of a drug into and across the skin?A chemical species will naturally diffuse across

a boundary or into an adjacent concentration

of different chemical species by passive diffu-

sion. Broadly speaking this is represented by a

chemical’s diffusion coefficient. When looking

at systems that involve permeation across a

membrane or into the skin, flux according to

Ficks’ laws is most applicable as a theoretical

modelling system, simplified to:

J=kpcapp

(where, J is flux, kp is the permeability

coefficient, and Capp

is the applied dose).

According to Fick’s laws the most important

factors that influence flux across the skin are

the concentration gradient of the drug between

the formulation and the skin, the partition coef-

ficient of the permeate and the diffusion coef-

ficient (Thomas and Finnin, 2004; Hadgraft,

2004).

In addition, the flux of a molecule across

a membrane should increase linearly with

concentration until capp

(applied dose) reaches

the solubility limit; the point of saturation

(i.e. a thermodynamic activity (TA) of 1).

Diffusion rates are also routinely faster for low-

11

Figure 1: Anatomy of the epidermis.

12 www.ondrugdelivery.com Copyright © 2013 Frederick Furness Publishing Ltd

melting-point compounds. In the past, these

laws were often forgotten and hence resulted

in the poor efficiency of delivery from such

formulations that limits the efficacy of many

topical products.

In summary, the higher the thermodynamic

activity of the active within the formulation (upon

application), the more efficient the delivery. This

is the case for all such formulations applied to

the skin. This approach (originally theoretically

conceived by Higuchi) has been used in the

development of supersaturated systems where

the thermodynamic activity of the drug in the

formulation exceeds unity (TA>1) by using

non-solvents and/or antinucleating polymers.

However, such approaches have failed in

the past because of the inherent chemical

and physical instability of the drug (i.e. it

crashes out).

Our MedSpray technology uses a different

approach. It is an aersolised spray that upon

actuation and evaporation of the propellant and

various co-solvents produces a film on the skin

surface containing the drug in a high or supersatu-

rated activity state, thus overcoming the instabil-

ity issues observed previously. It also contains a

clever combination of commonly used enhancers

which improves the delivery even further.

Q: What are the potential applications of MedSpray?

As we have already shown, MedSpray is a fun-

damental advance in how actives can be deliv-

ered topically for application locally to treat

dermal infections, inflammation, pain, psoriasis,

atopic dermatitis, acne etc, and for transdermal

delivery. The parameters in the drug-release

profile can be changed according to drug release

and penetration requirements.

Basically, MedSpray is a new hybrid between

an aerosol dosage form and a transdermal patch or

film. We term this technology Patch-in-a-can™.

It is sprayed on to the surface of the skin and

forms a microfilm, where it can deliver the drug

over a short or long time (extended or modified

release) depending on the preferred profile. The

properties of the film can be designed according

to the disease being treated, e.g. occlusive and

hydrating for psoriasis. In addition, the fact

that MedSpray can be sprayed directly onto the

skin means it does not have to be rubbed in or

manipulated and thus there is no chance of an

infection being spread or of cross contamination,

a problem common with the more traditional

dosage forms. In addition, MedSpray can also be

designed so that the patient feels cooling upon

application which can help in the relief of certain

symptoms such as itch and pain.

As such, MedPharm has currently tested

MedSpray up to and including Phase II trials

using a number of actives including ibuprofen,

diclofenac and a number of other NSAIDs, terbi-

nafine and other antimicrobials, antihistamines,

anaesthetics, methylphenidate, testosterone and

other steroids, fentanyl and buprenorphine, to name

but a few.

Q: How did MedPharm get involved in the development of novel delivery technologies?

It was always in our plan. MedSpray was our

first idea which is now patented throughout the

world including the US and Europe, and we

have continued to refine and adapt its versatility

to a wider variety of actives as it has been

licensed or as we have had the means internally.

A recent development is MedRo, where

MedSpray has been adapted to deliver drugs

locally or systemically via the oral mucosa.

Another delivery technology, MedTherm®, is in

its infancy but is as equally exciting. All such

technologies are available to our clients, with

the knowledge that they will have a patentable

product.

Q: Why did you see a need for these innovations?

Over the past 14 years at MedPharm we have

been given some challenging actives to formu-

late. It stands to reason that a new client would

give us candidates that they have found difficult

to formulate themselves. This is great as it tests

our mettle and forces us to expand the accepted

boundaries. We found that the existing arsenal

of formulation approaches, even with penetra-

tion enhancers, was simply not enough and we

needed new approaches to give the patient/con-

sumer what they want whilst increasing delivery

and efficacy. There is also a desire to move away

from potential irritants, greasy and impractical

ointments and creams along with cumbersome

and expensive delivery devices such as large

inefficient transdermal patches, needleless injec-

tors and proactive delivery devices such as

iontophoresis and electrophoresis which have

proven too impractical for routine use.

Q: Why would a drug manufacturer choose MedSpray to deliver their drug?

The advantages are pretty clear I think. Primarily

it’s a more effective vehicle for increasing deliv-

ery. Less of a reservoir of drug remains in the

vehicle on the skin unlike creams or ointments.

It’s also easier for the patient to apply as they

don’t have to touch the affected area with their

fingers and the resultant microfilm doesn’t leave

an obvious greasy residue. Patients also like it

since the evaporation of the volatiles has a cooling

effect on application. Finally it’s ideal for extend-

ed drug release where the active is delivered over

time. That’s why we developed a terbinafine

version and went all the way into a clinical trial

to show it provided cure after only one admin-

istration. I might add that all the excipients are

pharmaceutically acceptable and are approvable

in the EU and US and since we now have clinical

exposure in 120 patients we know there are no

skin-irritation or other toxicity issues.

Q: What other data have you got on the efficacy?

We have been working on this technology for a

number of years now and have acquired plenty

of drug release data in our models using differ-

ent actives. Some of it is still proprietary for

clients but we have shown the system to be both

Figure 2: Comparison of BDP release from MedSpray with a marketed cream using a synthetic membrane (mean ± standard deviation, n=5).

70.0

60.0

50.0

40.0

30.0

20.0

10.0

0.00 0.5 1 1.5 2 2.5

Time (hours)

Cum

ulat

ive

mas

s pe

r are

a (μ

g/cm

2)

3 3.5 4 4.5

MedSpray

Propaderm Cream

13Copyright © 2013 Frederick Furness Publishing Ltd www.ondrugdelivery.com

robust and versatile. For transdermal delivery we

have shown improvements in methylphenidate

uptake over Noven Therapeutics’ methypheni-

date patch, Daytrana®. Choosing hydrofluoroal-

kane (HFA) as a propellant was a critical point in

the development as this, unlike other propellants

previously used, is environmentally friendly and

non-flammable. We used a co-solvent system

to enhance drug solubility and anti-nucleating

agents which was another important step in

the development. We have data in our in vitro

performance testing models to show that we can

improve the release of betamethasone valerate

and beclametasone dipropionate (BDP) from

their original cream or mousse forms (see Figure

2). At each of the time-points taken, the quantity

of drug released across the membrane by the

spray was significantly greater compared to the

cream (<0.05 ANOVA). For instance, the flux

of the BDP MedSpray formulation was 30-fold

higher than the equivalent BDP cream

So in conclusion, there are many parameters

to consider when formulating a drug for

application to the skin that are not relevant to

oral or parenteral forms. However, the benefits

in patient compliance, ease of use and targeted

action outweigh the difficulties and with the

new delivery technologies that are advancing,

drug companies may be following this route of

administration with a closer eye in the future.

Q: You also talked about MedTherm. How does this compare?

In addition to the saturation principle we have

also looked at active methods of boosting

diffusion through the application of locally

raised temperatures. This has resulted in an

ongoing development we call MedTherm. We

apply the drug in a device or formulation that

self-generates local heat on application (similar

to the heat patches you can buy) but that also

contains a combination of enhancers. These

thermogenic formulations enhance delivery

through the skin through a synergistic effect

of thermophoresis on the enhancers which in

combination increases the passive diffusion

kinetics of the drug and disrupts the lipid

lamellae in the SC causing the layer to become

more fluid (Silva et al, 2006). It has also been

postulated that the heat increases local blood

flow through dilation of the blood vessels

which aids absorption (Hull, 2002; Osigo et

al, 1998). In our ex vivo performance-testing

models we have already shown a 75-fold

increase in the delivery of lidocaine into

human skin and are now following this up

with a comprehensive project to develop a

MedTherm topical version of methotrexate, a

notoriously difficult compound to formulate.

Temperatures of just over 40°C are achievable

and effective, and this is actually fairly pleasant

on the affected skin, producing a soothing anti-

pruritic effect.

Q: You have mentioned your in vitro / ex vivomodels a couple of times. Why are these models so important to MedPharm?

At MedPharm we have developed and validated

a versatile range of performance testing models,

a lot using human tissue, that help us to optimise

our formulations and also to demonstrate how

the formulations are going to perform when

they enter clinical evaluation. This provides our

clients with some confidence that when they

spend vast sums of money for the necessary

clinical trials, the projects will not fail; it

reduces risk. In addition, for skin indications it is

probably easier and more pertinent to use in vitro

/ ex vivo human skin models, such as the Franz

cell, than testing on animals, whose skin is very

different to that of humans. MedPharm has also

developed human skin models of disease which

our clients use to select the right drug to progress

and to get an indication of formulation efficacy.

Our toxicity models provide our clients with

the knowledge of any potential risk of toxicity,

e.g. irritation, when they enter the clinic. Again,

such models also minimise any animal testing

that may have to be performed; something

critical for MedPharm. I believe MedPharm has

become one of the world leaders in developing

these models and in some cases our models have

provided competent authorities with enough

evidence to circumvent the need for extended

bioequivalence trials for certain formulations.

As such MedPharm’s performance testing

facility which includes all these models has just

doubled in size and capacity to accommodate

our clients’ requirements.

REFERENCES

1. “Skin Disease Treatment Technologies &

Global Markets”, BCC Research, May 2013.

2. “North American Drug Delivery Technologies

Market (Metered Dose Inhalers, Needle-Free

Injectors, Auto-Injectors, Nasal Sprays,

Transdermal Patches, Nebulizers, Infusion

Pumps, Drug Eluting Stents, Sustained

Release, Ocular Implants) - Forecasts To

2017”, Markets and Markets, July 2013.

3. http://www.fiercepharma.com/special-

reports/15-best-selling-drugs-2012

4. Moser, K, Kriwet, K, Froehlich C, Naik

A, Kalia YN, Guy, R, “Permeation

enhancement of a highly lipophilic drug

using supersaturated systems”. J Pharm Sci,

2001, Vol 90, pp 607-616.

ABOUT MEDPHARM

MedPharm, based in Guildford, Surrey, UK, has

worked with more than 150 clients in the design

and development of topical formulations and medi-

cal devices for drug delivery, including both trans-

dermal patches and metered-dose inhalers. The

company has contributed to the development of

numerous new and generic products including 15

products that have since gained market approval.

Its expertise has always been in the design and

performance testing of topically and transdermally

delivered drugs.

MedPharm has carved a niche amongst

the worldwide contract research providers

in this field contributing to formulations

for application to the skin, nail, eye, airway

and mucosal surfaces and covering all semi-

solid dosage forms, foams, sprays, patches,

aerosols, and many other devices. MedPharm’s

experience over the past decade in topical and

transdermal formulation design has highlighted

new opportunities in today’s competitive market

for such routes as an alternative to parenteral

and oral drug delivery.

Professor Marc Brown Chief Scientific Officer, Chief Operating OfficerT: +44 1483 457580

MedPharm LtdR&D CentreUnit 3 / Chancellor Court 50 Occam Road Surrey Research Park Guildford, GU2 7AB United Kingdom

Professor Marc Brown, PhD, CChem, FRSC, co-founded MedPharm, the contract development and manufacturing organisation (CDMO) in 1999 as a spin-out of King’s College London, where he had previously been a Senior Lecturer in the School of Pharmacy. He maintains his links with academia with professorial positions at the UK Universities of Hertforshire, Reading and Dundee. Previously he had worked in the pharmaceutical industry in North America where he managed the development and approval of several topical formulations. To date he has been involved in the pharmaceutical development of 20 products that are now on the market in Europe, America and Japan including, Solaraze®, Zyclara® and Picato®. It has been during the creation and growth of MedPharm that he has witnessed most acutely the changes in formulation design, drug delivery and regulatory aspects for topically (locally acting) and transdermally (systemic) delivered drugs.

www.medpharm.co.uk

MedPharm are a highly experienced team of pharmaceutics, formulation development and drug delivery experts. We have helped the very largest down to the youngest companies to formulate their actives in to eff ective, safe, and stable topical & transdermal formulations. We off er a fully integrated service for development with projects ranging from feasibility studies, formulation, dosage & assay design optimisation through to preparation of cGMP clinical supplies.

Unique drug absorption optimisation platform technologies licensable for use with Client’s own actives:

MedSpray® AquaRMed™ MedTh erm®

Established 1999.

GMP compliant.

In Vitro performance testing laboratories.

More than 150 Clients worldwide.

15 formulations now marketed products.

Excised skin, cell culture, RHE, and synthetic membrane topical models.

www.MedPharm.co.uk

Number 1 in Topical & Transdermal DrugDelivery. Dermatologicals & Cosmetics Oral mucosal drugs Inhaled Ophthalmics Transdermal Patches Medical Device Testing

Th e Specialist CDMO for your formulation design, in vitro performance testing & clinical supplies manufactured in our own UK based cGMP facility.

Chancellor Court 50 Occam Road Guildford Surrey GU2 7AB UKPhone: +44 (0)1483 457580Email: [email protected]

MEDPHARM - TOPICAL & TRANSDERMAL EXPERTS

Medpharm.indd 1 30/09/2013 22:42


Here, Laurent-Dominique Piveteau, PhD, MBA (INSEAD), Business Development Director, Debiotech, describes the application of the company’s NanoPUMP™ technology in the design and development of JewelPUMP™, a wearable device for the continuous infusion of insulin, comprising a micro-engineered delivery system with advanced failsafe and safety features, a touchscreen patient interface, and mobile phone technology. Already in clinical trials as a deliv-ery system, development of JewelPUMP™ is also being taken forward for incorporation with a continuous glucose monitor into an artificial pancreas technology. Beyond insulin, this dispos-able patch pump can be used in other areas such as patient-controlled analgesia, Parkinson’s disease and parenteral delivery of high-dose biopharmaceuticals.

DISPOSABLE PATCH PUMP FOR ACCURATE DELIVERY

Pumps are commonly used today in many

therapeutic areas for the injection of active drug

substances. They can be found in the hospital

setting, in the emergency and operating rooms,

and at the bedside, but also increasingly at home

with patients managing their own treatment

daily. In this context, the quest for smaller

pumps, able to provide specific administration

profiles while being easy to use and comfortable

for the patient, is growing. These pumps are

used for chronic, long-term therapies, such as

infusion of insulin for diabetes, or apomorphine

for Parkinson’s disease, but also for acute

single or infrequent injections, for example,

of peptides, or biopharmaceutical drugs that

cannot be made available in sustained-release

form. Development of such products is more

challenging than it seems at first, in particular to

provide a smaller, more convenient disposable

product – to remove all maintenance work by

the patient – while maintaining the same levels

of safety and accuracy as those

available with large precision

electro-mechanical systems. In

addition, such new drug delivery

systems should also provide a

record of patient compliance,

preferably in real-time or over

the cloud.

SAFETY, ACCURACY, CONVENIENCE

Debiotech has been

developing innovative drug

delivery systems for more than

23 years. One of its proprietary

platforms, the NanoPUMP™, is particularly

suited for this type of applications because

of its unique precision integration and

miniaturisation. Based on a microfabricated

silicon chip, so called Micro Electro

Mechanical System (MEMS), it is currently

used as the engine for a device targeting

complex Continuous Subcutaneous Infusion of

Insulin (CSII): the JewelPUMP™. This product

is currently subject to further development for

other drug applications.

Dr Laurent-Dominique PiveteauDirector, Business Development

Debiotech SA“Le Portique”28, avenue de SévelinCH-1004 LausanneSwitzerland

T: +41 21 623 60 00F: +41 21 623 60 01E : [email protected]

www.debiotech.com

“COST EFFICIENCY IS ALSO OF ESSENCE

IN THE MEMS INDUSTRY. AS AN

EXAMPLE, ON AN EIGHT-INCH WAFER

THERE ARE UP TO 375 NANOPUMPS

PRODUCED AT ONCE. THE STANDARD

SIZE OF A PRODUCTION BATCH IS

25 WAFERS, REPRESENTING A TOTAL

AMOUNT OF 9,375 PUMPS”

Copyright © 2013 Frederick Furness Publishing Ltd www.ondrugdelivery.com 17

The pumping mechanism of the NanoPUMP™ comprises a

miniaturised MEMS membrane pump (10x6 mm2) (see Figure 1). This

pump, comprising a pump chamber having a stroke volume of 200 nl,

two valves located on both sides of the pumping chamber, and two strain

gauge sensors, is mounted on a ceramic substrate and is driven by a

bending low power consumption piezo-electric actuator (see Figure 2).

This component weighs less than 2g and is made out of silicon, a highly

biocompatible material. It can, in its current design, pump fluids of

various viscosities at rates up to 2.5 ml/h with an accuracy better than 5%

at all delivery rates (Figure 3).

This pumping mechanism is connected to a disposable container with

enough capacity for several days of therapy and an electronics containing

all the elements necessary to drive and control the injection profile with all

required information and alarm means. This assembly forms a completely

sealed, waterproof, miniaturised device within an optimal physiological

shape, which can be placed directly on the patient’s skin (Figure 4). The

drug is injected into the intradermal space through a flexible cannula

directly connected to the pump.

The reservoir is a semi-rigid element made of a plastic component

acting as a sort of backbone on which the pumping mechanism is attached

together with a welded thermoformed membrane constituting the drug

reservoir. It contains a patented membrane filter ensuring the automatic

priming of the pump as well as the retention of any air bubble in the

reservoir. The plastic component contains the entire fluidic path: access

to fill the reservoir, passage between the reservoir and the pumping

mechanism and connection of the pump to the injection site. This path is

design to minimise dead volume. Thanks to the resulting high compression

ratio, the device can pump compressible fluids such as air, and is therefore

self-priming. This high degree of integration also allows for both a more

compact pump packaging, and a major simplification of the assembly

process and thus a reduction of production costs.

Constant and accurate flow-rate is guaranteed through the control

of the displacement of the pumping membrane. The movement occurs

between two mechanical stops defined by the construction of the chip:

the flow rate is linear with actuation frequency and virtually insensitive

to inlet and outlet pressure, actuation voltage, temperature, viscosity and

aging. The outlet valve is equipped with a safety device – an anti free-

flow valve – that blocks the outlet under abnormal pressure conditions

in the reservoir. Thanks to a drug reservoir always maintained at normal

ambient pressure, the pump is protected against any potential harmful

over-delivery. Additionally the pump is equipped with two built-in

Figure 1: The MEMS pumping unit: 10x6 mm2.

Figure 2: Cross section of the MEMS chip of the NanoPUMP™ showing the inlet valve (a), the pumping chamber (b), the first (c) and second (d) detectors and the outlet valve (e). The MEMS chip is attached to a ceramic substrate on which electrical connections are printed.

Figure 3: The MEMS pumping mechanism mounted on a ceramic substrate: the heart of the NanoPUMP™.

Figure 4: The NanoPUMP™ applied on a patient’s body.

Figure 5: The JewelPUMP™ and its remote control.


sensors monitoring the pumping at each stroke level. Abnormal conditions

such as occlusion, presence of air, end of reservoir, anomalous leaks are

immediately detected and reported, allowing for fast action. The pump is

also designed to be waterproof for as little interference as possible with

the patient’s normal life.

The pumping mechanism is manufactured in close partnership with

ST Microelectronics in its state-of-the-art facilities located in Italy and

Malta. Each single pump is fully tested: in few seconds, the stroke volume

is measured and the integrity and tightness of the entire pump is verified.

The complete system is covered by twenty five families of patents that

ensure exclusivity for Debiotech until 2033.

THE JEWELPUMP™: AN IMPLEMENTATION OF THE NANOPUMP™

The NanoPUMP™ is the heart of the JewelPUMP™, a medical device

currently being developed by Debiotech to be used for the treatment of

Type 1 diabetes (another version targeting Type 2 diabetes is currently

in development). Type 1 diabetes is an autoimmune disease in which

the islets of Langerhans present in the pancreas and producing insulin

have become nonfunctional. Insulin is an essential element for the proper

functioning of cells metabolism as it governs their ability to absorb glucose

from the blood and use it as source of energy.

The standard treatment for these patients is the replacement injection

of insulin. A typical delivery profile comprises a basal rate, covering the

necessary requirements for the vital functions and representing about the

half of total daily dose, and several times a day larger bolus injected over

a short period to cover the needs generated by sugar intake and meals.

A pump designed for insulin delivery shall therefore be able to inject over

a very broad range of rates, from less than 5 μl/h up to 200 μl in a few

minutes. In addition, the profile will vary between patients and for a given

patient it must be adapted from one day to the next, depending on his

health, his physical activity, the content of his meals ... These adjustments

are made by the patient himself. It is therefore necessary to provide the user

with a very easy and ergonomic programming interface. Finally, insulin is

a very potent drug and its plasma concentration must be maintained within

a very narrow window; over-delivery as well as under-delivery can lead to

very serious conditions, sometimes to death.

The JewelPUMP™ (shown in Figure 5) is based on the

NanoPUMP™construction. A disposable reservoir including the pumping

mechanism is connected to a reusable controller. The reservoir has a

volume of 5 ml and can contain 500 U of insulin, an amount sufficient

Figure 6: The remote control of the JewelPUMP™.

Figure 7: Screenshots of the remote control.

“THE STUDY, WHICH INVOLVES SEVEN

RESEARCH CENTRES IN FRANCE, IS

AIMED AT DEVELOPING NEW ALGORITHMS

FOR A CLOSED-LOOP SYSTEM, ALSO

CALLED AN ARTIFICIAL PANCREAS.

IN SUCH A CLOSED-LOOP SYSTEM, THE

INFUSION PUMP IS CONNECTED TO A

CONTINUOUS GLUCOSE METER (CGM)

THAT REGULARLY MEASURES THE PATIENT’S

BLOOD-GLUCOSE CONCENTRATION”


for a week’s treatment. This represents more

than twice the capacity of existing pumps. The

controller can be used for two years. It comes

in different colours which can be adapted by

discretion to the colour of the patient’s skin

or, on the contrary, be chosen as a fashion

accessory. The entire pump has an external

volume of approximately 60x40x14 mm3 and a

total weight of less than 25g.

The pump contains a first sensor that

monitors the temperature of the insulin present

in the reservoir and advises the patient in

case of over exposure to heat (for example,

being left in the sun), as well as a second

activity and position sensor for potential

automatic treatment adjustments. It can be

freely attached and detached during treatment,

according to patient needs. The patient just

has to slide the pump onto a patch adapter

that is connected to the flexible cannula. The

system will automatically detect that is has

been disconnected and then reconnected, and

as such will stop and then resume the infusion.

The pump also integrates an alarm system

combining both sound and vibration. This

combination allows for discreet information

for low-priority messages, while ensuring that

the patient is alerted in case of an emergency.

The pump is programmed with a remote

control (Figure 6) incorporating a large

colour touchscreen and communicating

through a Bluetooth BLE protocol with the

pump. Particular attention was paid to the

development of the graphical user interface and

the technological capabilities of the touchscreen

were used to their fullest (Figure 7). Based on

an Android OS platform, the programming

of the pump is very intuitive. The software

includes functionalities to assist the patient

in determining his insulin needs and to send

relevant information to the caregiver. To avoid

any confusion, fonts of different sizes were

used to discriminate units from subunits and

each submenu has a specific colour; the patient

knows immediately in what submenu he is. The

security of data exchange has also been pushed

to its maximum by integrating into the pump

electronics a unique SIM card that will create an

almost inviolable communication link between

the pump and the remote controller.

CLINICAL RELEVANCE

The JewelPUMP™ has been tested by

many diabetic patients in both Europe and the

US. These patients were already using pumps

or had refused to, or stopped, using pumps

following a negative experience. They were

given the opportunity to wear, manipulate

and program the pump. The general feedback

was very positive with more than 85% of

patients wanting to switch immediately to the

JewelPUMP™.

The pump is also in a multicentre clinical

study with more than 50 patients to date.

The study, which involves seven research

centres in France, is aimed at developing

new algorithms for a closed-loop system,

also called an artificial pancreas. In such a

closed-loop system, the infusion pump is

connected to a continuous glucose meter

(CGM) that regularly measures the patient’s

blood-glucose concentration. In response to

variations in this concentration the system

will adapt the quantity of delivered insulin:

the amount is increased in case of growing

Figure 8: Graphs showing the deviation of the “real delivery rate” from the programmed rate for the JewelPUMP™ (a) and a durable syringe drive pump (b). As can be seen, the JewelPUMP™ always remains within ±5% from the programmed rate, while the syringe drive system presents under delivery of 45% over 30 minutes and over deliveries of nearly 40% over 30 minutes.


glucose concentration or stopped to avoid

hypoglycaemia. The ability of such a closed-

loop system to deliver a treatment safely lies

in the accuracy of each of its elements. It

is essential that the exact dose of insulin is

delivered in response to the measured glucose

level otherwise this could lead to a subsequent

wrong decision by the algorithm.

While on average, over 24 hours, current

wearable pumps can infuse a drug precisely,

events of more than 30 minutes with over-

or under-delivery of more than 30% occur

regularly (see Figure 8). Unfortunately, this

30-minute window corresponds to the reaction

time of current closed-loop systems. A poor

accuracy in the delivery method will lead to

dramatic instabilities. Closing the loop with

accurate pumps should therefore lead to a

significant improvement in the quality and

reliability of these systems.

Diabetic patients consider undetected

occlusions as one of the most dramatic types

of events that may occur during CSII. If

handled in a wrong way, this may lead to coma

and potentially to death. With its integrated

detector placed within the pumping element, the

JewelPUMP™ can detect occlusion after just

one pump-stroke, i.e. after only 200 nl or 0.02

units of insulin have been missed. It becomes

possible to give an early and unambiguous

alarm to the patient, allowing him to take any

action to liberate the occlusion in a safe way.

CONCLUSION

Drug infusion pumps are still often

cumbersome and complex devices. They are

adapted for involved and motivated patients

and can be used only after a long training.

This has limited drastically their use for

therapies outside of Type 1 diabetes and this

despite a growing number of studies showing

much better outcomes when treatments are

conducted with pumps compared with classical

methods. The disposable NanoPUMP™ with

its small size, low cost, ease of use and

convenience is offering a real solution to

democratize the use of pumps in a large

number of therapies, with simple or complex

delivery profiles, and potentially improving

compliance. The most evident application

is certainly Type 2 diabetes, a form of the

disease hitting an older population that often

refuses its condition and looks for therapies

perceived as noninvasive.

Beyond insulin, the pump could be used

for example in the management of pain in

patient controlled analgesia (PCA), in the

treatment of Parkinson’s disease through

infusion of apomorphine, to conduct various

hormonal treatments or also for the parenteral

delivery of some high-dose biopharmaceutical

formulations. Even a prefilled drug option could

be considered, based on highly biocompatible

material used. For all these markets and several

others, the NanoPUMP™ has a great potential

for success.

ABOUT DEBIOTECH

Debiotech SA is a Swiss Company with

more than 20 years’ experience in developing

highly innovative medical devices, based

on micro- and nanotechnology, micro-

electronics, and innovative materials. The

company concentrates on implantable and

non-implantable systems, in particular for drug

delivery and diagnostics, with a demonstrated

competence lying in the identification of

breakthrough technologies and their integration

into novel medical devices.

Devices developed by Debiotech are

eventually licensed to major international

pharmaceutical and medical device companies,

with a track record of over 40 license agreements

worldwide. Examples of products in addition to

the JewelPUMP™ for diabetes care include

the I-Vantage™ IV pump for hospital and

home-care, the CT Expres™ Contrast Media

injector for CT-Diagnostic Imaging (recently

acquired by Bracco Imaging), the NanoJect™

microneedles for intradermal injections, the

DialEase™ home-care miniaturised dialysis

equipment, and others under development.

MICRO-ELECTRO MECHANICAL SYSTEM (MEMS)

MEMS is a manufacturing method that uses technologies developed by the semiconductor

industry to create mechanical and electrical structures in wafers made of single-crystal silicon. A

combination of photolithography, etching and deposition processes is used to create structures in

the sub-micrometre range in a highly reproducible manner and in very high volumes. All these

processes are conducted in an ISO class 5 cleanroom environment. At this scale silicon is both

mechanically resistant and elastic. It is therefore possible to create structures such as flexible

membranes that will support millions of actuations without showing signs of fatigue. Cost

efficiency is also of essence in the MEMS industry. As an example, on an eight-inch (20 mm)

wafer (Figure 9) there are up to 375 NanoPUMPs produced at once. The standard size of a

production batch is 25 wafers, representing a total amount of 9,375 pumps. Thanks to this very

high parallelization in the manufacturing process, it is possible to reach high cost effectiveness.

Figure 9: The different wafers forming a NanoPUMP™.

“BEYOND INSULIN, THE PUMP COULD BE USED,

FOR EXAMPLE, IN PATIENT CONTROLLED ANALGESIA

(PCA), IN PARKINSON’S DISEASE THROUGH INFUSION

OF APOMORPHINE, TO CONDUCT VARIOUS HORMONAL

TREATMENTS OR ALSO FOR THE PARENTERAL DELIVERY OF

SOME HIGH-DOSE BIOPHARMACEUTICALS”


In this article, Sari Prutchi Sagiv, PhD, Marketing Director at TheraCoat, explains why longer chemotherapy dwell-time is critical for the opti-mal treatment of bladder cancer, and how this can be achieved via a simple yet sophisticated drug delivery system.

GREAT INVENTIONS THAT TRICK NATURE – NEW DELIVERY SYSTEM OPTIMISESBLADDER CANCER TREATMENT BY INCREASING DWELL TIME

INTRODUCTION

Theracoat’s Internal Cavity Drug Retention

(ICDR) system allows for controlled and high-

ly effective delivery of therapeutic agents into

the bladder without being voided and diluted

by the urine, overcoming the major drawbacks

of instilled therapies. ICDR defies some natural

norms regarding the behaviour of materials.

Normally, gels become liquid with heat, not

the other way around. Based on advanced

materials technologies, the novel ICDR system

stays liquid outside the body when cooled,

and becomes a muco-adhesive gel only once

inside the bladder. The use of the ICDR system

increases drug exposure and reduces toxicity,

significantly enhancing treatment potential,

safety and compliance.

BLADDER CANCER

Bladder cancer is the fourth most frequent

solid tumour cancer in men and the seventh

in women, with more than 350,000 new

cases diagnosed worldwide annually with a

prevalence of 840,000 patients in Europe and

530,000 in the US. Most patients suffer from a

non-invasive disease with a high survival rate

but high recurrence rates mean lifelong treat-

ment and monitoring.

Around 35% of the non-muscle invasive

bladder cancer (NMIBC) tumours recur within

one year after surgical removal. As a con-

sequence, NMIBC patients have to undergo

periodical and expensive follow-up, making

NMIBC the most expensive cancer to treat

on a lifetime basis.1 The cost per patient

from diagnosis to death can reach US$120,000

(£75,000), translating to a $3.8 billion annual

spend in the US.

The initial treatment of this cancer is surgi-

cal removal of the tumour, commonly known

as transurethral resection of the bladder tumour

(TURBT) followed by a series of periodic intra-

vesical chemotherapy instillations which the

patient is required to retain for approximately

60 minutes. Intravesical chemotherapy is used

either as an adjuvant to TURBT, to delay tumour

recurrence, or to control widespread disease not

manageable by surgical methods.2 The rationale

is to expose tumours to high local drug concen-

trations while minimising systemic exposure,

enhancing treatment efficacy and reducing drug

toxicity. But these traditional approaches to

treating bladder cancer have largely proven to be

insufficient since after intravesical instillation,

drug concentration is immediately reduced and

washed out due to continuous urine creation and

voiding. Therefore, the cancerous tissue is not

optimally exposed to the drug, allowing tumour

reseeding and migration.

The improved efficacy of chemotherapy fol-

lowing increase in tissue exposure time (dwell

time) was established by numerous in vitro

models,2-4 in vivo studies,5 and computer simu-

lations.6 Schmittgen showed that tumour sen-

sitivity increases with increasing Mitomycin

Dr Sari Prutchi SagivMarketing DirectorT: +972 77 4171412E: [email protected]

TheraCoat13 HaSadna StreetRaananaIsrael

www.theracoat.com

“AFTER TRADITIONAL INTRAVESICAL INSTILLATION, THE DRUG

CONCENTRATION IS IMMEDIATELY REDUCED AND WASHED

OUT DUE TO CONTINUOUS URINE CREATION AND VOIDING”


C (MMC) exposure time.4 De Brujin treated

bladder cancer patients with intravesical MMC

using 30- and 60-minute dwelling times.5 He

demonstrated that recurrence was significantly

lower in the 60-minute treatment group. No

recurrences were found in patients with low

grade tumours when the 60-minute dwelling

time was used. These results were supported by

numerous studies conducted by Barlogie et al,

Slee et al, Ozawa et al and Perry et al.7-10

Based on this data, Badalament’s suggestion

for optimisation of the efficacy of intravesical

chemotherapy included holding the dosing solu-

tion as long as possible (“Have the patient hold

the intravesical therapy in his bladder as long as

possible”) and dehydration of patient for reduc-

ing urine production (“Dehydrate patients prior

to intravesical therapy”).11

Prolongation of intravesical treatment dwell

time is imperative for enhancing the anti-tumour

effect of the instilled chemotherapy.

PROLONGING DWELL TIME

The novel ICDR system addresses these cur-

rent treatment drawbacks. The system employs

a novel hydrogel with unique thermo-sensitive

properties which enable it to convert from a

liquid state when cold into a gel at body tem-

perature. In its liquid state, ICDR can easily be

mixed with a specific drug for convenient cath-

eter delivery into the bladder (as performed in

the standard intravesical chemotherapy). Once

inside the bladder, it solidifies, adheres to the

mucosal layer and forms a drug reservoir. Upon

contact with urine the gel reservoir dissolves

and gel micelles entrapping the drug adhere to

the mucosal layer of the bladder.

The drug is slowly released, keeping high-

er and effective tissue drug concentration for

a longer period of time (approximately 6-8

hours). During the release of the drug, the gel

is slowly dissolved and no traces of the gel are

present after the treatment period. Since the gel

dissolution is gradual, the gel delays the voiding

of the drug from the bladder once the first uri-

nation occurs (in contrast to the standard intra-

vesical chemotherapy) as well as decreases drug

dilution by the ongoing produced urine which

continuously enters the bladder (Figure 1).

ICDR CHARACTERISTICS

ICDR is a thermo-sensitive hydrogel with

reverse thermal gelation (RTG) properties: it

has high viscosity at body temperature and very

low viscosity (fluid like) at 5°C. This temper-

23

“PROLONGATION OF INTRAVESICAL TREATMENT

DWELL TIME IS IMPERATIVE FOR ENHANCING THE

ANTI-TUMOUR EFFECT OF THE INSTILLED CHEMOTHERAPY”

Figure 1: Drug intravesical instillations with and without ICDR. With ICDR, the drug concentration is kept for longer.

Figure 2: When used with ICDR a) the level of Mitomycin C (MMC) in the tissue two and six hours following instillation was 11-13 fold higher compared with drug alone (same total dosage), and b) the levels of MMC in the plasma were significantly lower than drug instilled alone.

a)

b)


ature-dependent viscosity characteristic allows

for simple instillation of the cooled liquid gel

into the bladder.

The hydrogel is formulated solely with well-

known ingredients, approved by the US FDA as

inactive ingredients and widely used as excipi-

ents in numerous commercial formulations. The

hydrogel is 100% biocompatible.

Following mixing with a drug, the gel it is

capable of storing the drug without changing the

drug structure and activity. It is considered inert

with no expected chemically modifying interac-

tion within the gel and between the gel and its

loaded drug. The gel formulation can be eas-

ily adjusted and tailored for retention of various

drugs and delivery rates ranging from 3-24 hours.

The amphiphilic nature of ICDR facilitates

incorporation of both hydrophilic and hydro-

phobic drugs.

It is water soluble, insensitive to pH, and

also muco-adhesive and flexible, complying

with the natural volume and shape changes of

the internal cavity under treatment

PRECLINICAL & CLINICAL STUDIES

ICDR was shown to causes no damage to the

bladder, ureter or urethral tissues (preclinical

results) and had no significant effect on instil-

lation safety (preclinical and clinical results).

Studies in large animals (pigs) testing intra-

vesical instillation of MMC in ICDR demon-

strated a lower systematic exposure to MMC

in comparison with standard treatment. MMC

plasma levels were far below the blood toxic

MMC levels. The lower systematic exposure of

TheraCoat’s treatment suggest that TheraCoat’s

treatment has the potential to lower adverse

event rate and lower side effects leading to high-

er patient compliance. In addition, gel residues

with MMC were detected in the pig bladder

six hours following instillation, supporting the

retention capabilities of the TheraCoat system.

Thus, the preclinical results demonstrate that

ICDR increases the availability of MMC to the

tissue and prolong its exposure duration (Figure

2a) while decreasing MMC exposure to the sys-

temic circulation (Figure 2b).

Clinical safety studies with patients follow-

ing single or multiple instillations with ICDR

with and without MMC showed:

• Smooth injection of gel through catheter

• Catheter removal five minutes post instillation

• No bladder contraction due to gel instillation

• Free urination and no obstructive symptoms

• No study-related adverse events.

Preliminary results from ongoing clinical

studies show efficacy of the delivery sys-

tem in tumour ablation in low-grade blad-

der cancer patients. Figure 3 demonstrates

a complete response to treatment (tumours

were completely removed) in a patient

after six weekly instillations of MMC with

TheraCoat’s ICDR.

FUTURE DIRECTIONS

Current treatments for bladder diseases,

including bladder cancer, comprise local intra-

vesical drug instillations, but these treatments

have largely proven to be insufficient. Scientific

literature strongly supports that the longer the

tumour tissue is exposed to chemotherapy the

more effective it is to kill cancer cells, but once

a drug is delivered into the bladder, it is quickly

diluted and excreted due to continuous urine

creation and voiding. Thereby, a clear unmet

need exists for means to prolong drug retention

and tissue exposure in order to improve efficacy.

TheraCoat effectively overcomes current

treatment drawbacks and has developed a new

proprietary drug delivery system for local treat-

ment of bladder diseases. The novel hydrogel-

based system enables controlled and longer expo-

sure of bladder tissue to therapeutic agents as

compared with standard intravesical instillations.

In addition to bladder cancer, TheraCoat is

currently developing improved delivery modes

for a number of bladder diseases including

upper tract urothelial carcinoma, interstitial

cystitis and overactive bladder.

REFERENCES

1. Botteman MF, Pashos CL, Redaelli A, Laskin

B, Hauser R, “The health economics of blad-

der cancer: a comprehensive review of the

published literature”. Pharmacoeconomics,

2003, Vol 21(18), pp 1315-1330.

2. Walker MC, Masters JRW, Parris CN,

Hepburn PJ, and English PJ, “Intravesical

Chemotherapy: In Vitro Studies on the

Relationship Between Dose and Cytotoxicity”.

Urol Res, 1986, Vol 14, pp 137-140.

3. Serreta V, “Optimizing intravesical chemother-

apy in patient with non-muscle invasive blad-

der carcinoma”. Archivio Italiano di Urologia

e Andrologia, 2008, Vol 80(4), pp 143-147.

4. Schmittgen TD, Wientjes MG, Badalament

RA, Au JL, “Pharmacodynamics of Mitomycin

C in Cultured Human Bladder Tumors”,

Cancer Res, 1991, Vol 51, pp 3849-3856.

5. de Bruijn EA, Sleeboom HP, Peter JRO,

van Helsdingen PJRO, van Oosterom AT,

“Pharmacodynamics & Pharmacokinetics of

Intravesical Mitomycin C Upon Different

Dwelling Times”. Int Journal Cancer, 1992,

Vol 51(3), pp 359-364.

6. Au JLS, Jang SH, Wientjes MG, “Clinical

Aspects of Drug delivery to Tumors”. J

Controlled Release, 2002, Vol 78, pp 81–95.

7. Barlogie B, Drewinko B, “Lethal & Cytokinetic

Effects of Mitomycin C on Cultured Human

Colon Cancer Cells”. Cancer Res, 1980, Vol

40, pp 1973-1980.

8. Slee PHThJ, De Bruijn EA, Leeflang P,

Kuppen PJK, van den Berg L, van Oosterom,

“Variations in exposure to mitomycin C in an

in vitro colony-forming assay”. Br J Cancer,

1986, Vol 54, pp 951-955.

9. Ozawa RJ, Sugiyama Y, Mitsuhashi Y,

Kobayashi T, Inaba M, “Cell Killing Action

of Cell Cycle Phase-Non-Specific Antitumor

Agents is Dependent on Concentration-Time

Product”. Cancer Chemother Pharmacol,

1988, Vol 21, pp 185-190.

10. Perry RR, Greaves BR, Rasberry U, “Effect

of Treatment Duration and Glutathione

Depletion on Mitomycin C Cytotoxicity

in Vitro”. Cancer Res, 1992, Vol 52, pp

4608-4612.

11. Badalament RA, Farah, RN, “Treatment of

Superficial Bladder Cancer With Intravesical

Chemotherapy”. Seminars in Surgical

Oncology, 1997, Vol 13, pp 355-341.

Figure 3: After six weekly instillations of MMC mixed with ICDR, the tumours were completely removed in a patient with superficial bladder cancer.Photo courtesy of Dr Sudhir K Rawal, Director Surgical Oncology & Chief of Surgical Gynae Uro-Oncology, Rajiv Gandhi Cancer Institute and Research Centre, India.

Novel drug delivery solutions for the optimal treatment of bladder diseases Sustained release of drugs within internal cavities

Novel Reverse-Thermal Gelation technology

Increased tissue exposure to drugs

Reduced systemic toxicity

theracoat.com

Redefining Entropy

Entropy - \’en-tra-p˜\ Natural property of disorder in a system with increasing temperature

• Products & clinical programs for Non Muscle Invasive Bladder Cancer (NMIBC), Upper Tract Urothelial Carcinoma (UTUC), Interstitial Cystitis (IC), and Overactive bladder (OAB)

thera redone.indd 1 27/09/2013 13:40


ONdrugDelivery 2013/14 EDITORIAL CALENDAR

Publication Month Issue Topic Materials Deadline

October 2013 Prefi lled Syringes Issue now closed

November 2013 Pulmonary & Nasal Drug Delivery (OINDP) Extended

December 2013 Delivering Biotherapeutics November 4th

January 2014 Ophthalmic Drug Delivery December 9th

February 2014 Prefi lled Syringes January 13th

March 2014 Transdermal Patches, Microneedles & Needle-Free Injection February 10th

April 2014 Pulmonary & Nasal Drug Delivery March 10th

May 2014 Injectable Drug Delivery 2014: Devices Focus April 14th

June 2014 Injectable Drug Delivery 2014: Pharmaceutics Focus May 12th

July 2014 Novel Oral Delivery Systems June 9th

September 2014 Drug Formulation & Delivery, Services & Solutions 2014 August 4th

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In this article, Mahesh Chaubal, PhD, Senior Director, Drug Development, R&D Medical Products, Baxter Healthcare Corporation, provides a glimpse of some of the challenges faced dur-ing the development of viscous formulations of biopharmaceutical products for injection, from a formulator’s perspective, especially when the finished product is filled in a prefilled syringe.

PREFILLED SYRINGES FOR VISCOUS FORMULATIONS

Prefilled syringes represent a patient-friendly

and compliant way to administer drugs in an

alternate setting such as the home. This makes

them an appropriate device for drugs that are

administered chronically.

Prefilled syringes have gained popularity over

last two decades due to the emergence of biologics

as a major class of injectable therapeutics.1

Today, biologics are used for the treatment of

various acute and chronic conditions. For chronic

conditions, the final dosage form should be patient

friendly, such that the patient can self-administer

and avoid the costs of using a healthcare provider.

However, a downside of chronically administered

drugs is the frequency of injections. In an effort

to reduce the frequency of injections, formulators

often try to load a significant dose in a single

injection that must then be delivered. High-dose

formulations pose significant challenges from a

formulation and fill-finish perspective.

Typically, drug stability over the duration of

the product’s shelf-life is a formulator’s main

focus. However, when developing dosage forms

for self-administration, additional factors have

to be taken into consideration. These include

performance of the device over the shelf-life,

and the human factor aspects of the device

usability. The importance of the latter is visible

in the US FDA’s guidance on using human

factors for medical devices.2

For viscous formulations, device

performance and human factors become

even more important, given that a viscous

formulation may be harder to administer via a

prefilled syringe. The interplay between these

various factors is demonstrated in this brief case

study for developing a viscous formulation in a

prefilled syringe format.

FORMULATOR PERSPECTIVE

High-concentration drugs that are

administered chronically are formulated

to provide sustained release. This can be

achieved via either the use of a release rate

modifier or intrinsically long half-life of the

drug. Release-rate modifiers include polymers

formulated as microspheres or gels, as well as

oily depots wherein the drug is dissolved in

pharmaceutically acceptable oil. In each case,

the release-rate modifier (or high concentration

of the drug) result in a formulation that has high

viscosity.3 Figure 1 lists some of the potential

drug formulations that involve high viscosity.

When dealing with highly viscous

formulations, the end-user perspective

is important upfront at the formulation

development stage. Highly viscous formulations

cause challenges during various process steps,

such as transfer operations (pumping) and Dr Mahesh V. ChaubalSenior Director, Drug Development, R&D Medical ProductsT: 1 847 270 6657

Baxter Healthcare Corporations25212 W. Illinois Route 120Round LakeIL 60073United States

www.baxterbiopharmasolutions.com

Type of viscous formulation Example product

Polymer-solvent gels Eligard

Polymer solutions Hyalgan

Oily formulations Faslodex

Microspheres Lupron depot

High concentration MAbs Kineret (150 mg/mL)

Figure 1: Table listing examples of marketed high viscosity formulations available in prefilled syringes.


filtration, among others. If the final container

closure is a prefilled syringe, then high viscosity

can also cause problems with the syringeability

of the final formulation.

Syringeability or injectability is the ability/

ease by which a formulation can be dispensed

out of a syringe. Currently, no harmonised

approach exists for testing the syringeability

of a drug. Limited literature data is available

that describes various approaches for evaluating

syringeability.4-6 Formulators often mistakenly

assume a direct correlation between syringeability

and viscosity and hence use viscosity of the drug

solution as a surrogate measure of syringeability.

In this study, syringeability from a BD Hypak

glass prefilled syringe was measured directly using

the Hagen-Poiseuille equation, which is used to

assess the pressure differential across a pipe during

flow. In this case, flow through a needle as the

formulation is pushed out is analogous and hence

justifies the use of this equation:

ΔP = 8QLμ/πr4 where P is the pressure across the needle, Q

is the injection speed, μ is the viscosity of the

formulation, L is the length of the needle and r

is the radius of the needle.

As can be seen in Figure 2, during

formulation optimisation studies for an oily

depot formulation, a direct correlation could

be obtained between the viscosity of the

formulation and the respective syringeability of

the product from a prefilled syringe.

In order to assess the viability of syringing

this viscous formulation, the viscosity of the

formulation was compared with other viscous

products. Figure 3 shows that when the viscosity

of the formulation was compared with another

commercially available viscous product, Hyalgan

(sodium hyaluronate; Fida, Italy), it was observed

that while the two formulations had similar

viscosity, there was a significant difference in

their syringeability. Hyalgan is a formulation of

hyaluronic acid which is a thixotropic polymer

gel.7 Hence viscosity of the formulation decreases

during the syringing process. Another product

listed in Figure 1, Eligard (leuprolide acetate;

Sanofi, France), utilises the shear thinning property

of poly(lactic-co-glycolic acid) (PLGA) solutions

to reduce the viscosity of the formulation prior

to administration.8 This demonstrates that while

viscosity is an important formulation parameter, it

is not always indicative of the syringeability of the

product and hence specific studies are required in

the prefilled syringe of choice.

Given the high syringeability forces required

for the test article, the formulation was modified

by changing the oil-drug ratio and also by adding

a solvent to reduce viscosity. This resulted

in a formulation that demonstrated acceptable

forces for syringeability of the product through

a typical BD Hypak glass syringe.

SUMMARY

Prefilled syringes are a preferred container

closure system for delivery of chronically

delivered formulations, due to ease of

administration in an alternate setting, such as at

home. However, this format adds complexities,

compared with the conventional vial format.

This report provides a case study of the interplay

between formulation development and fill-finish

configuration development. It is essential for the

two activities to occur simultaneously to develop

an effective product. In this specific case, an

effective formulation in prefilled syringe was

developed by manipulating the oil-to-cosolvent

ratio of the oily depot formulation.

Use of the appropriate fill-finish partner

is important in developing such complex

formulations. Baxter’s BioPharma Solutions

business has in-house capability to support

formulation development and fill-finish aspects

of viscous formulations in prefilled syringes.

REFERENCES

1. Adler M, “Challenges in the Development

of Pre-filled Syringes for Biologics from a

Formulation Scientist’s Point of View”. Am

Pharm Rev, Vol 15(1), Feb 2012.

2. “Use of human factors for medical device

evaluation.” (http://www.fda.gov/humanfactors)

3. Larsen S, Thing M, Larsen C, In “Long

Acting Injections and Implants” J. Wright

and D. Burgess (Eds), Adv Del Sci & Tech,

2012, pp113-135.

4. Cilurzo F, Selmin F, Minghetti P, Adami

M, Bertoni E, Lauria S and Montanari L,

“Injectability evaluation: an open issue”.

AAPS PharmSciTech, 2011 (June), Vol 12(2),

pp604–609.

5. Allahham A, Mainwaring DE, Stewart P,

Marriott J, “Development and application

of a micro-capillary rheometer for in vitro

evaluation of parenteral injectability”. J

Pharm Pharmacol, 2004, Vol 56, pp709–716.

6. Chien YW, Przybyszewski P, Shami EG,

“Syringeability of nonaqueous parenteral

formulations--development and evaluation of

a testing apparatus”. J Parenter Sci Technol,

1981, Vol 35(6), pp281–284.

7. Matteini P, Dei L, Carretti E, Volpi N, Goti A, Pini

R, “Structural behavior of hyaluronan under high

concentration conditions”. Biomacromolecules,

2009, Vol 10(6), pp1516-22.

8. Eligard® prescribing insert, Sanofi-Aventis

US LLC, 2010.

28

Formulation Viscosity Syringe DP Instron Force Measurement (N)

Cp psi Mean force, 1 mL Mean force 3mL

Hyalgan 284 3.94 2.3 NP

Castor oil 912 25.1 NP 90.9

Test article 283 12.85 6.9 37.8

Figure 2: Relationship between viscosity and syringeability for an oily formulation injected using a glass prefilled syringe.

Figure 3: Comparison of viscosity and syringeability of an oily depot formulation with a commercial viscous product.

14

12

10

8

6

4

2

00 50 100 150

Viscosity (cs)

y=2.0783e0.0059x

Syrin

geab

ility

(psi

)

200 250 300

“Best Contract Manufacturing Organization” BioPharma Solutions Wins Best CMO at Vaccine Industry Excellence Awards For Three Years Consecutively (2010, 2011, 2012)

920810-00 1/12

For more information, visitbaxterbiopharmasolutions.com

or visit us at ICSE 2013 – Booth 42G21

baxter redone.indd 1 30/09/2013 22:27


In this short article, Michelle Amaral, PhD, Science Writer/PR Consultant, Soluble Therapeutics, summarises some of the techniques available for the generation of different formulations of recombinant protein therapeutics, and high-throughput technologies that reduce the time required to screen for the optimal formulation.

PROTEIN SOLUBILITY CAN BE ENHANCED AT VARIOUS POINTS ALONG THE PRODUCTION PIPELINE

A revolutionary moment for the pharmaceutical

industry occurred with the advent of recombinant

technologies, which enabled proteins to be

manufactured and then delivered to humans or

animals for the purpose of treating illness and

disease. As a result, a wide range of therapeutic

approaches opened up: aberrant proteins

causing a disease state could be replaced; novel

proteins combatting a particular disease could

be introduced; and delivery of small-molecule

pharmaceuticals could be enhanced through

conjugation to a protein or antibody.

In the late 1970s, insulin was the first human

protein to be produced using genetic engineering

technologies and became commercially

available in 1982, greatly advancing the

treatment of diabetes. However, the use of

proteins in therapeutic strategies presents a

number of challenges, namely the requirement

that a protein be highly concentrated, stable, and

active in solution when delivered.

Fresh, innovative approaches are now

providing valuable solutions for protein

pharmaceuticals. The aforementioned challenges

can be confronted at various points along the

path of protein production. In the early stages

of development, a protein’s solubility can be

affected by the choice of expression vector and

the option of adding a fusion tag to the protein

of interest. Further downstream, self-interaction

chromatography (SIC) is being used as a fast

and effective method for determining the most

optimal formulation of a protein solution.

The selection of a high-performance expression

vector is a must when creating a strategy for

recombinant protein production, as it can play

an integral role in promoting a soluble product in

addition to an optimal yield. In many cases, these

vectors encode for extra amino acids that are

then attached, or fused, to the protein of interest

upon expression. The result is a fusion protein

with greater solubility than that of the native

macromolecule expressed alone. Oftentimes, the

fusion partner even contains a region of histidine

“tags” that enable quick, efficient purification

with affinity chromatography and a cleavage

site that allows its subsequent removal using a

specific protease treatment.

A fusion partner can range in size from

a few amino acids to approximately 25 kDa.

The added residues create disorder, allowing

greater distance between each protein molecule

and thus giving the protein of interest “space”

to fold properly. This process enhances

solubility of the target protein and prevents

aggregation. Activity assays have been

performed on numerous representative proteins,

demonstrating that functionality is preserved.

Protein solubility can also be enhanced after

its production by formulating a buffer solution

with conditions that are optimal for proper folding

and stability. This is an important step along

Dr Michelle AmaralScience Writer/PR ConsultantT: +1 205 206 4600F: +1 205 449 2551E: [email protected]

Soluble Therapeutics, Inc1500 1st Avenue NorthBirminghamAL 35203United States

www.soluble-therapeutics.com

31Copyright © 2013 Frederick Furness Publishing Ltd www.ondrugdelivery.com

the pipeline, as protein pharmaceuticals must

be highly concentrated so efficacious levels

can be reached when delivered to a patient.

At such high concentrations, however, proteins

have a tendency to precipitate out of solution,

aggregate, or form a highly viscous phase -

all of which are not amenable to storage or

delivery of the drug, since the protein’s activity

becomes compromised. Unfortunately, standard

recipes for these formulations do not exist, and

the conditions for each protein can vary greatly.

Each component must be determined empirically,

varying such characteristics as pH, additives,

and salt concentration. But with such an array of

components from which to choose, finding optimal

formulations can prove to be a monumental task

requiring upwards of one year to complete.

Self-interaction chromatography has been

recently introduced as a powerful method

for developing highly concentrated protein

formulations – and in just a matter of weeks.

SIC is a technique that measures the extent

of a protein’s interaction with itself, and its

applicability is generally unaffected by the

vast array of additives available to the typical

formulation professional.

Other methods of measuring protein-protein

interactions are sometimes limited because of

the light scattering effects of some additives.

SIC requires a small amount of protein that is

covalently attached to beads and packed into

a microcapillary HPLC column. The mobile

phase of the SIC experiments consists of the

formulation being tested, along with a 1 μl bolus

injection of the protein of interest. The elution

of the protein injected in the mobile phase is

measured via UV detection and the retention time

is used to evaluate whether or not the formulation

or additive of interest is causing attraction or

repulsion between the protein molecules.

Data collected via SIC enables the

calculation of a parameter that quantitatively

describes the protein’s interaction with itself;

this is the second virial coefficient, or B value.

The B value is the sum of all potential forces

between two proteins including ionic, dipole,

hydrophobic, and van der Waals forces; it is a

measure of protein flexibility in all orientations

and distances. In general, positive B values

indicate a net repulsion between two protein

molecules while negative B values indicate a

net attraction. When additives are introduced

into solutions, the B value is altered such that

the protein molecules display mild attraction to

each other, which is conducive to crystallisation,

or enhanced repulsion, which increases the

protein’s physical stability and solubility.

Experimentally determined B values can

be used to predict the B value of a protein

in over 12,000 other formulations using an

artificial neural network. This is a wealth of

information for groups that are developing a

new biopharmaceutical. Differential scanning

calorimetry and other biophysical techniques

are performed to confirm a complete

characterization profile on the final solutions.

Treatments for disease have drastically

improved since the advent of protein

therapeutics. In order to be successful, though, a

protein must be highly concentrated, stable, and

active in solution without aggregation or other

phase changes that are detrimental to the drug

delivery process and the patient. Solubility can

be enhanced at several points along the protein

production pipeline. Creating disorder by

fusing extra amino acid residues to the protein

of interest generates distance between each

molecule, enhancing the ability of the protein

to fold correctly. An optimal formulation for

the protein of interest is crucial for protein

performance as well.

High-throughput methods that screen

components of the solution save time and money

for a company developing a promising drug.

Maximizing Your Innovation.

Collaboration & Strategic Value-Added Capabilities to jointly select, design, clinically test and commercialize the right delivery system for your drug.

Industry-Leading Devices utilizing advanced therapeutic and patient-centric research – to optimize ergonomics, intuitive use and safety – and ultimately simplify the patient experience and improve compliance.

Integrated Design through Commercialization resulting in strict adherence to technical specifications through rigorous design and verification to full-scale manufacturing.

Expertise & Resources to Manage Downside Risk by providing consultative support for worldwide regulatory submissions, expertise in human factors engineering, and a proven track record offering devices with global freedom to operate safeguarded by strong IP protection.

At BD, we can help you maximize your potential, minimize your risk, and realize the success you’ve worked so hard to achieve. Contact a BD expert today at 1-800-2 5-3310 or [email protected] Learn more at: www.bd.com/self-injection

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Your drug is your innovation. From discovery to commercialization, your commitment is a tireless endeavor. That’s why BD is committed to delivering your new therapy in a manner that fully supports your goals.

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